During fetal life the respiratory epithelium produces lung liquid by a process involving active chloride (Cl-) secretion. After birth distal lung epithelial cells absorb sodium (Na+) and water. The successful absorption of fetal lung liquid during birth is essential for effective postnatal pulmonary gas exchange. Absorption of liquid during birth and maintanence of relatively dry airspaces after birth requires a transition from prenatal Cl- secretion to postnatal Na+ absorption. The overal objective of the proposed work is to clarify the mechanisms and the regulation of this transition. The work will identify and determine thc relative importance of different pathways for the movement of ions across the distal lung epithelium during development and examine the role of various hormones relevant to birth and lung development in regulating ion transport. The specific aims are to measure changes in Na+ and Cl- transport by freshly isolated and cultured distal lung epithelial cells isolated from fetal, newborn and adult rabbits; to determine the effects of selected ion transport inhibitors and potential regulatory hormones on Na+ and Cl- transport by these cells; and to make correlative measurements of lung luminal liquid movement in living fetal sheep. These studies involve the coordinated use of 3 complementary experimental models to assess ion transport by distal lung epithelial cells and the importance of changes in ion transport by these cells to the movement of lung liquid during birth. They involve measurement of radiolabelled ion uptake by freshly isolated and cultured cells, measurement of bioelectrical properties (transepithelial electrical potential difference, short-circuit current, and resistance) of cultured cell monolayers, and measurement of lung luminal liquid secretion and absorption in living fetal animals. The proposed project will include experiments designed to assist in relating information from one experimental model to another. These complementary models allow for the evaluation of ion transport at 3 different levels of tissue organization (cellular, epithelial and organ levels) during development. This integrated approach is essential to attaining a thorough understanding of the relationship between developmental changes in ion transport by distal lung epithelium and the removal of liquid from the airspaces of the lung at birth. Such understanding may have important implications concerning perinatal lung liquid balance and disease states where abnormal alveolar fluid balance plays a role.